DK171415B1 - Process for Preparing Vitamin A - Google Patents

Description

DK 171415 B1

The present invention relates to a process for preparing vitamin A so that the stereochemistry of the starting material is retained in the final product.

Vitamin A and its carboxylic acid esters, typically the acetate and palmitate, are used in large amounts such as e.g. medications and feed additives. The following methods have previously been proposed for the preparation of vitamin A and its carboxylates.

10 (1) Helvetica Chimica Acta 3J), 1911 (1947) cich2co2ch3;

25 JIa Vitamin A hydros— Vitamin A

? acetate (wherein Ac = acetyl group) (2) Chemie Ingenieur Technik 4_5, 646 (1973).

q a ·

. Vitamin A hydrolysis_ »Vitamin A

NaOCH 3 'acetate f 5 (wherein Ph = phenyl group, X = halogen atom,

Ac = acetyl group) (3) Helvetica Chimica Acta 59, Vol. 2, 387 (1976)

(1) HCsCH v RS ° 2M

(2) H2 in OH (M = Na or Lir

C₂O ^ * 1.1 ”·· 111 ^

R

I O-S-O j base v „. ^ X

^^ O ^^^ - OAc -> Vitamin A

(wherein Ac = acetyl group) (4) J. Org. Chem. 41, 3287 (1976) rV ^^ O (1) HC = CH v HX x

Uk ~ ^ ι— * Uk iH * is + Λ ^ οη.

S02Ar? Sodium amide excess (5 equiv.)

in liquid ammonia_) Vitamin A

containing tert.butyl alcohol 3 DK 171415 B1

The conventional methods for the preparation of vitamin A described in (1) to (4) use all beta-ionone as starting material. Beta-ionone is industrially prepared by cyclizing pseudo-ion using a large amount of concentrated sulfuric acid. Since the yield of beta-ionone is not so high and it is difficult to distinguish from the by-product alpha-ionon, e.g. In distillation, however, beta-ionone is not always available at low cost.

It is the object of the present invention to provide a process for the preparation of vitamin A of the formula H3CCH3? H3? H3

, _> S ^ CH-CH-C-CH-CH = CH-C-CH-CH, OH

0 such that the stereochemistry of the starting material is retained unchanged in the final product.

According to the present invention, this object is achieved by providing a process which is characterized in that a compound of the general formula 25 ^ h3c αζΓ «3« 3 21 3 '> <^ ch-ch-c = ch -ch2ch2-c = ch-ch2orz ^ (Ha-2) CJC OR3 V ^ CH, 3 ° R1 0 = S = 0 ptj ru HC CH-j IT 3 7 3 21 3 ^ <j ^ CH-CH «C- CH-CH2CH2-C = CH-CH2OR (in Ib) 35 or 3 4 DK 171415 B1 R1 0 = S = 0 ΛΙ1 H, C CH, |, 3, 3 22 3 X ^ C * CH-C = CH-CH -CHo-C = CH-CH-OR '(Ile)' O 'wherein R1 represents a phenyl group optionally substituted, R21 and R22 each represent a hydrogen atom or a lower alkanoyl group, R3 represents an acetal type protecting group for a hydroxyl group, and X represents a halogen atom, are treated with a base selected from lower alkoxides of potassium and potassium hydroxide in a solvent selected from aliphatic hydrocarbons and aromatic hydrocarbons and mixtures thereof.

The above starting materials of formulas (IIa-2), (IIb) and (Ile) are readily available, inexpensive industrial products.

The term "phenyl group optionally substituted" means, as used herein for R 1, an unsubstituted phenyl group or a substituted phenyl group having 1-5, preferably one or two, substituents. Examples of such substituents include lower alkyl groups, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl, and lower alkoxy groups such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and tert-butoxy, as well as halogen atoms such as chlorine, bromine or iodine. Specific examples of a "phenyl group which may be substituted" include phenyl, o-tolyl, m-tolyl, p-tolyl, p-ethylphenyl, pn-propylphenyl, p-isopropylphenyl, pn-butylphenyl, 2,4-dimethylphenyl, p-methoxyphenyl, 2,4-dimethoxyphenyl, p-chlorophenyl and p-bromophenyl, of which a phenyl and a p-tolyl group are particularly suitable as R1.

The term "lower alkanoyl group" encompasses, as used, e.g. formyl, acetyl, propionyl and butyryl groups.

5 DK 171415 B1

The term "acetal-type protecting group for a hydroxyl group", as used herein, may be any ordinary acetal-type protecting group commonly used to block the reactivity of the hydroxyl group (OH) by a chemical reaction. Specific examples of the protecting group include a tetrahydropyran-2-yl group, a 4-methyl-tetrahydropyran-2-yl group, a tetrahydrofur-2-yl group and lower alkoxyalkyl groups such as methoxymethyl, 1-methoxyethyl, 1-ethoxyethyl, 1- n-propoxy-O-ethyl and 1-n-butoxyethyl.

The term "lower", as used herein to describe a group or compound, means that the group or compound so described does not have more than 6, preferably no more than 4, carbon atoms.

The term "halogen atom", as used herein, means fluorine, chlorine, bromine and iodine atoms. The halogen atom for X is preferably chlorine and bromine.

In the process of the invention, vitamin A of formula (I) can be obtained by treating the compound with Formula (IIa-2), (IIb) or (Ile) with a base. Examples of the base are lower potassium alkoxides such as potassium methoxide, potassium ethoxide, potassium isopropoxide, potassium n-propoxide, potassium n-butoxide and potassium t-butoxide, and potassium hydroxide.

The amount of base used is not critical and can be varied over a wide range according to e.g. the type of the starting material of formula (IIa-2), (IIb) or (Ile) and / or the base type. Usually it can be from approx. 2 to approx. 30 moles, preferably from ca. 2 to approx. 10 moles, especially from ca. 3 to approx. 6 moles, pr. mole of compound of formula (IIa-2), (IIb) or (IIle).

Usually the reaction is carried out in a solvent, e.g. an aliphatic or aromatic hydrocarbon such as hexane, heptane, cyclohexane, benzene or toluene. They can be used either individually or in combination

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tion. The amount of the solvent is also not critical. Generally, it is advantageous for the amount to be such that the concentration of the compound (IIa-2), (IIb) or (Ile) in the solvent will be from ca. 0.05 to approx. 1 mol, preferably from ca. 0.1 to approx. 0.5 mol, per liters of solvent.

The temperature at which the above-mentioned treatment is carried out can be varied depending on e.g. the type of compound (IIa-2), (IIb) or (Ile) and / or the type of base. Generally, a suitable temperature is from approx.

0 ° C to approx. 100 ° C, preferably from ca. 20 ° C to approx. 80 ° C. Usually, the treatment is preferably conducted in an atmosphere of an inert gas such as helium, nitrogen or argon.

In the above treatment with base, vitamin A is formed in good yields from a compound of formula (IIa-2), (IIb) or (Ile). The resulting vitamin A of formula (I) can be isolated and separated from the reaction mixture by known methods. For example. water or an aqueous solution of ammonium chloride is added to the reaction mixture and the organic layer is separated from the mixture. If necessary, the organic layer is washed with water and / or dried with anhydrous sodium sulfate, and / or the solvent is evaporated at reduced pressure to separate vitamin A. If necessary, the product can be subjected to a purification process, such as recrystallization, to obtain vitamin A of high purity. .

The compounds of formula (IIa-2), (IIb) and (Ile) used as starting material in the above process are novel compounds not previously described in the literature. They can be prepared by the following methods.

35

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DK 171415 B1 7

Compound of Formula (IIa-2)

This compound can be prepared by steps which comprise reacting a compound of the formula 5 H, C

(III) CH ^ where R · is as indicated above, with a compound of the formula CH3CH3O = c-c = ch-ch2ch2-c = ch-ch2or2 (IV)

H

2 where R is a lower alkanoyl group, in the presence of a base to form a compound of formula 20 R1 0 = S = 0 ΛΒ H, C CH, | , 3 .3 2 3 'XV ^ CH-CH-C = CH-CH, CH, -C = CH-CH9OR (IIa-1)

OC OH

Wherein R and R are as indicated above, introducing an acetal-type protecting group for OH in this compound and, if necessary, solvolysis of the resulting compound under non-acidic conditions.

The compound of the general formula (III) is commonly used in an amount ratio of from approx. 0.1 to approx. 10 moles, preferably from ca. 1 to approx. 2 moles, pr. moles of the compound of general formula (IV).

The base to be present in the reaction system during the reaction between compound (III) and compound (IV) is a base which can produce a carbanion at the carbon atom to which the group -SC is bound in the compound (III). Specific examples include organolithium compounds such as methyl lithium and n-butyllithium, organomagnesium halides (Grignard reagents) such as methyl magnesium chloride, methyl magnesium bromide, ethyl magnesium chloride and ethyl magnesium bromide, alkali metal hydride, alkali metal hydride, such as lithium hydride, such as lithium hydride, such as lithium hydride. sodium amide and potassium amide, as well as lower alkali metal alkoxides such as lithium methoxide, sodium methoxide, potassium methoxide, potassium ethoxide and potassium t-butoxide. The amount of the base is not critical and can be varied depending on e.g. the type of base used.

Generally, it is from ca. 0.1 to approx. 1 mol, preferably 0.5-1 mol, per ml. moles of the compound of formula (III).

The above reaction is usually carried out in a solvent. The solvent is suitably selected, taking into account its combination with the base, from e.g. aliphatic or aromatic hydrocarbons such as hexane, heptane, benzene and toluene, aliphatic or cyclic ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethylformamide, N-methylpyrrolidone, dimethylsulfoxide and hexamethylphosphoric acid triamide.

25

The reaction is carried out at a temperature of usually from ca. -100 ° C to approx. 150 ° C, preferably from ca. -80 ° C to approx. 50 ° C, although the temperature may vary depending on the base used. Advantageously, the reaction is conducted in an atmosphere of an inert gas such as helium, nitrogen or argon. The reaction time may vary depending on e.g. the base, solvent or reaction temperature. When the reaction is carried out at a temperature of approx. -80 ° C to approx. -50 ° C in tetrahydrofuran using n-butyl-35

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DK 171415 B1 9 lithium as a base, the reaction time is e.g. from approx. 2 to approx. 6 hours.

The compound of formula (IIa-1) can be separated and recovered from the reaction mixture by conventional methods. For example.

5, water, an aqueous solution of ammonium chloride or dilute hydrochloric acid is poured into the reaction mixture and the organic layer is separated. If necessary, the organic layer is washed with water and / or dried over anhydrous sodium sulfate and / or the solvent is evaporated. Subsequently, the product 10 is subjected to a purification step, such as recrystallization or chromatography, to isolate the compound of the general formula (IIa-1).

The compound of formula (IIa-1) can be converted to 21 a compound of formula (IIa-2) wherein R is a lower alkanoyl group, e.g. reacting the compound (IIa-1) with a vinyl ether such as 3,4-dihydro-2H-pyran, 4-methyl-3,4-dihydro-2H-pyran, 2,3-dihydrofuran or a lower alkyl vinyl ether such as methyl vinyl ether, ethyl vinyl ether, propyl vinyl ether or butyl vinyl ether, in the presence of an acidic catalyst or reaction of the compound of formula (IIa-1) with methylal in the presence of e.g. phosphorus pentoxide. The reaction of the compound of formula (IIa-1) with the vinyl ether does not necessarily have to be carried out in a solvent. However, it is usually preferably carried out in a solvent such as methylene chloride, tetrahydrofuran, diethyl ether or benzene. As the acid catalyst, e.g. p-toluene sulfonic acid, its pyridine salt, sulfuric acid or hydrochloric acid.

Preferably, p-toluenesulfonic acid or its pyridine salt is used. When 3,4-dihydro-2H-pyran, 4-methyl-3,4-dihydro-2H-pyran or 2,3-dihydrofuran is used as the vinyl ether in this reaction, a compound of formula 21 3 (IIa) can be obtained. 2) wherein R is a lower alkanoyl group and R is a tetrahydropyran-2-yl group, a 4-methyl-tetrahydropyran-2-yl group or a tetrahydrofur-2-yl group. When the lower alkyl vinyl ether is used as the vinyl ether, a 21 compound of formula (IIa-2) is obtained, wherein R is a lower alkanoyl group and R is a 1-lower alkoxyethyl group.

On the other hand, it is achieved by the influence of

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methylal on the compound of formula (IIa-1) in the presence of e.g. phosphorus pentoxide is a compound of formula (IIa-2), wherein R is a lower alkanoyl group and R is a methoxymethyl group.

The compound of formula (IIa-2) wherein R represents a lower alkanoyl group prepared by the above reactions can be separated and recovered from the reaction mixture by conventional methods. For example. water is poured into the reaction mixture and the mixture is extracted with an organic solvent such as benzene, diethyl ether or ethyl acetate. The extract is washed with water and dried over anhydrous sodium sulfate. Low boiling points are evaporated from the extract at reduced pressure and the residue is chromatographed on a silica gel column. As a result, the compound of formula (IIa-2) wherein R is a lower alkanoyl group can be isolated.

The resulting compound of formula (IIa-2), wherein R is a lower alkanoyl group, can be directly treated with the base. However, if desired, the compound can be solvoluted under non-acidic conditions and the resulting compound of formula (IIa-2) wherein R represents a hydrogen atom can be treated with the base. Solvolysis of the compound ice of formula (IIa-1) wherein R represents a lower alkanoyl group may be carried out in a solvent, e.g. an alcohol such as methanol or ethanol, or a mixture of the alcohol with water and / or a hydrocarbon such as benzene or toluene, preferably in the presence of an alkali metal hydroxide, carbonate or alkoxide. Examples of an alkali metal hydroxide or carbonate are potassium hydroxide, sodium hydroxide, lithium hydroxide, potassium carbonate, potassium methoxide or sodium methoxide. The amount of the alkali metal hydroxide, carbonate or alkoxide is preferably from ca. 1 to approx. 2 equivalents based on the compound 21 of formula (IIa-2) wherein R is a lower alkanoyl group.

The amount of the solvent is preferably such that the concentration of the compound of formula (IIa-2), 21 wherein R is a lower alkanoyl group, is from about 10 0.1 to approx. 10 moles per liters of solvent. When a mixture of an alcohol with water and / or a hydrocarbon is used as a solvent, the water and / or the hydrocarbon should preferably be used in such an amount that no phase separation is induced in the reaction system. The reaction is conveniently carried out at a temperature of from ca. -10 ° C to A 30 ° C. The compound of formula (IIa-2) wherein R 1 is a hydrogen atom can be separated from the reaction mixture by conventional methods. For example. a saturated aqueous solution of ammonium chloride, dilute hydrochloric acid or dilute sulfuric acid is added to the reaction mixture to neutralize the remaining alkali metal hydroxide or carbonate. If necessary, the solvent used as solvent is evaporated.

Water is added to the residue and the mixture is extracted with an organic solvent such as benzene, methylene chloride, diethyl ether or ethyl acetate. The extract is washed with water and dried over anhydrous sodium sulfate. Then, low-boiling substances are evaporated as needed from the extract at reduced pressure. The residue is chromatographed on a silica gel column, whereby a compound of formula (IIa-2), 21 wherein R is a hydrogen atom, can be isolated.

The compound of formula (III), which is used as a starting material in the preparation of the compound of formula (IIa-2), is a known compound (JP-A-1,168,158) and can be readily prepared in good yields from linalool , which is a cheap industrial material. For example. For example, a compound of formula (III) wherein R 1 is a phenyl group can be prepared by the following method.

35 DK 171415 B1 12

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SOC1. I I £ VS02Na OH> -> 5 h2so4-ch3co2h ^ .. Cc ”· - ©

Specifically, the effect of thionyl chloride on linalol gives geranyl chloride, and the reaction of geranyl chloride with sodium phenylsulfinate gives geranylphenylsulfone. Geranyl-phenylsulfone is cyclized in the presence of an acidic catalyst, such as a mixture of sulfuric acid and acetic acid, to give beta-cyclogeranylphenylsulfone. In the cyclization reaction, alpha-cyclogeranyl phenylsulfone, an isomer for beta-cyclogeranyl sulfone, can sometimes be formed as a by-product.

However, high purity beta-cyclogeranyl phenyl sulfone can be obtained by crystallization of the resulting mixture of the two isomers in a solvent such as hexane. The alpha-cyclogeranylphenyl sulfone can be converted to beta-cyclogeranylphenylsulfone by being returned to the cyclization reaction system. The total yield of beta-cyclogeranylphenylsulfone from linalool is usually from about 10%. 70 to approx. 90%. The compound of formula (IV), the second starting material, can also be readily prepared in good yields from linalool. For example. For example, a compound of formula (IV) wherein R is an acetyl group can be prepared by the following method.

35

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Specifically, gives the effect of acetic anhydride on linealoolgeranyl acetate. The geranyl acetate is reacted with e.g. refluxing selenium dioxide in an ethanol solvent to give the desired 8-acetoxy-2,6-dimethyl-2,6-octadienal. The total yield of 8-acetoxy-2,6-di-methyl-2,6-octadienal from linalool is usually from ca. 60 to approx. 80%.

The compounds of formulas (IIa-1) and (IIa-2), prepared as described above, represented by the following formula 20 R 1

fu CH

· 3 · 3 21 X 3CH-CH-C = CH-CH-CH, -C = CH-CHoOR'iA (IIa) where R · * · means an aryl group which may be substituted, 21 4 3Q R means a lower alkanoyl group and R represents a 21 hydrogen atom or R represents a hydrogen atom or a 4 lower alkanoyl group and R represents an acetal type protecting group for a hydroxyl group are novel compounds not previously described in the literature. In formula (IIa), preferably, a phenyl or p -tolyl group, R is preferably a hydrogen atom or a 4 acetyl group, and R is preferably a hydrogen atom, a methoxymethyl group, a 1-ethoxyethyl group, a 1- n-butoxy-ethyl group, a tetrahydropyran-2-yl group or a 4-5-methyl-tetrahydropyran-2-yl group.

Compound of Formula (IJb)

This compound can be prepared by halogenating a compound of formula 10 R 1 0 -S-0 ΛΟ H, C CH, I 7 3, 3 o J> <^ CH-CH-C * CH-CH, CH - C = CH -CH, OR (I Ia-1) 0C ”15 1 2 where R and R are as above and prepared as described above and, if necessary, by solvolysis of the resulting compound under non-acidic conditions.

Halogenation of the compound of formula (IIa-1) 20 may be effected by the action of a halogenating agent thereon. Examples of a halogenating agent are thionyl halides such as thionyl chloride and thionyl bromide, and halogenated phosphorus compounds such as phosphorus trichloride, phosphorus tribromide, phosphorus pentachloride and phosphorus oxychloride. The amount of halogenating agent is not critical and can be varied depending on the type of halogenating agent used. Generally, a suitable amount of halogenating agent is from ca. 1 to approx. 10 equivalents, preferably 1-3 equivalents, based on the compound of formula (Ila-30 -1). The reaction is conveniently carried out in an organic solvent in the presence of a tertiary amine. Examples of an organic solvent are hydrocarbons such as benzene and toluene, halogenated hydrocarbons such as methylene chloride and 1,2-dichloroethane, ethers such as diethyl ether and diisopropyl ether, and esters such as ethyl acetate and butyl acetate. The amount of solvent is

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DK 171415 B1 is such that the concentration of the compound of formula (IIa-1) is from approx. 0.1 to approx. 5 mol. liters of solvent. As tertiary amine, advantageously, e.g. pyridine or triethylamine. The tertiary amine is preferably used in an amount of from about 0.01 to about 0.5

50 equivalents, based on the compound of formula (IIa-1). However, when used in excess, the tertiary amine can also serve as the organic solvent. The reaction is preferably carried out at a temperature of generally from -20 ° C to approx. 50 ° C, preferably from -10 ° C to 30 ° C. This reaction gives a compound of formula (IIb) wherein R is a lower alkanoyl group corresponding to R in the starting compound of formula (IIa-1). This compound can be separated from the reaction mixture by conventional methods. For example. For example, the reaction mixture is poured into water or a saturated aqueous solution of e.g. sodium bicarbonate or dilute sulfuric acid. Then the mixture is extracted with an organic solvent such as benzene, methylene chloride, diethyl ether or ethyl acetate. The extract is washed with water and dried over anhydrous sodium sulfate. Then, low-boiling substances are evaporated from the extract at reduced pressure. The residue is subjected to a purification step such as recrystallization or chromatography. As a result, a compound 21 of formula (IIb) wherein R is a lower alkanoyl group can be isolated.

The resulting compound of formula (IIb), wherein R is a lower alkanoyl group, can be directly treated with the base. However, the compound can, if desired, be solubilized under non-acidic conditions and the resulting compound of formula (IIa-2) wherein R is a hydrogen atom can be treated with the base. Solvolysis of compound 21 of formula (IIa-2) wherein R is a lower alkanoyl group can be carried out in the same manner as described above.

In the compound of formula (IIb) prepared as described above, R ovenfor is preferably a phenyl or p-21-tolyl group, R is preferably a hydrogen atom or an acetyl group, and X is preferably a chlorine atom. Compound of Formula (Ile)

This compound can be prepared by treating the compound of formula (IIb) prepared as described above with a dehydrohalogenating agent.

Examples of a dehydrohalogenating agent which can be used in this reaction include organic or inorganic bases, e.g. tertiary amines such as 1,8-diazabicyclo [5,4,0] undec-7-ene, 1,5-diazabicyclo [4,3,0] non-5-ene, 1,4-diazabicyclo [ 2,2,2] octane and N-methylmorpholine, and alkali metal hydroxides such as sodium hydroxide and potassium hydroxide. When a compound of formula (IIb) wherein R is a lower alkanoyl group is subjected to the action of a tertiary amine as a dehydrohalogenating agent, a compound of formula (Ile) wherein R is a lower alkanoyl group is obtained. When an alkali metal hydroxide is used as a dehydrohalogenating agent in a solvent containing a 22

alcohol, there is obtained a compound of formula (Ile) wherein R

is a hydrogen atom. When a compound of formula (IIb), wherein R is a hydrogen atom, is reacted with a dehydrohalogenating agent, a compound of formula (Ile), 22 wherein R is a hydrogen atom, is obtained. The amount of dehydrohalogenating agent used is not critical and can be varied depending on e.g. type of dehydrohalogenating agent and reaction conditions. It is usually from approx. 1 to approx.

10 moles, especially 1-5 moles, per moles of the compound of formula (IIb). This reaction will usually yield beneficial results when carried out in a solvent. The solvent is appropriately selected taking into account its association with the dehydrohalogenating agent. When a tertiary amine is used as a dehydrohalogenating agent, the solvent used is preferably a hydrocarbon such as benzene or toluene, a halogenated hydrocarbon such as methylene chloride or 1,2-dichloroethane, an ether such as diethyl ether or tetrahydrofuran, or an amide such as Ν, Ν-dimethylformamide and N-methylpyrrolidone.

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DK 171415 B1 17

The amount of solvent used is preferably such that the concentration of the compound of formula (IIb) is about 0.1 to approx. 5 moles / liter of solvent. The reaction is conveniently carried out at a temperature generally of about 0 to approx. 100 ° C, preferably 20 - 80 ° C.

When an alkali metal hydroxide is used as a dehydrohalogenating agent, the solvent used is preferably an alcohol such as methanol and ethanol, or a mixture of the alcohol with water and / or a hydrocarbon such as benzene or toluene. In this case, the amount of solvent used is preferably such that the concentration of the compound of formula (IIb) will be from approx.

0.1 to approx. 5 moles / liter of solvent. When a mixture of an alcohol with water and / or a hydrocarbon is used as a solvent, the water and / or the hydrocarbon should preferably be used in such an amount that no phase separation occurs in the reaction system. In this case, the reaction is conveniently carried out at a temperature of generally from ca. -20 ° C to approx. 50 ° C, preferably from -10 ° C to 30 ° C.

The compound of formula (Ile) obtained by the dehydrohalogenation reaction can be separated from the reaction mixture and purified by conventional methods. For example. 25 dilute sulfuric acid or an aqueous solution of ammonium chloride is added to the reaction mixture to neutralize the remaining dehydrohalogenating agent. If necessary, evaporate the solvent. Water is added to the residue and the mixture is extracted with an organic solvent such as benzene, toluene, methylene chloride or ethyl acetate.

The extract is washed with water and dried over e.g. anhydrous sodium sulfate. The solvent is then evaporated from the extract and the residue is chromatographed. As a result, the compound of formula (Ile) can be isolated.

A compound of formula (Ile) wherein R is a lower alkanoyl group, when obtained as such, can be converted to a compound of formula (Ile) wherein R is a hydrogen atom by solvolysis under non-soluble acidic conditions. The solar volysis can be performed as described above.

In the compounds of formula 5 (Ile) thus prepared, R 1 is preferably a phenyl or p-tolyl group, 22 and R is preferably a hydrogen atom or an acetyl group.

The stereochemistry of vitamin A prepared by the method of the invention depends on the stereochemistry of the compound of formula (IV) 10 CH3 CH3 O = C-C = CH-CH2CH2-C ** CH-CH2OR2 (IV ”)

H

15 where as indicated above. If a compound of formula (IV) is used in which the stereochemistry based on the carbon-carbon double bonds at the 2- and 6-positions is restricted to trans (E), then vitamin A, which is sterically restricted to exclusively, is obtained. trans. When a compound of formula (IV) is used in which the stereochemistry based on the carbon-carbon double bond at the 2-position is limited to trans (E) and at the 6-position to cis (Z), predominantly vitamin A is obtained. wherein the stereochemistry based on the carbon-carbon double bond at 13 position is limited to cis.

According to the present invention, by reacting the compound of formula (III) and the compound of formula (IV) which is readily prepared in good yields from linalool, a cheap industrial material, in the presence of a base, a compound of formula can be readily prepared (IIa-1) in high yields. In treating the compound of formula (IIa-2) or the compound of formula (IIb) derived from the compound of formula (IIa-1), or the compound of formula (Ile) derived from the compound of formula (IIb) ), with a base, a steric bound vitamin A dependent on the stereochemistry of the compound of formula (IV) can be readily obtained in high yields.

The following examples further illustrate the present invention.

EXAMPLE 1, "Q ·

BtHqB. , i'1, V, 1.9.

In a 200 ml three-neck flask, which is purged with nitrogen gas, add 10.80 g (38.8 mmol) of beta-cyclogeranyl phenylsulfone (2) and 100 ml of toluene, then 24.2 25 ml (25.6 mmol) of a diethyl ether solution of ethylmagnesium bromide (1.06 mol / liter) is added dropwise at a temperature in the mixture of 20-25 ° C. After the addition, the mixture is stirred at 40-45 ° C for 3 hours. The flask is then cooled so that the temperature of the mixture becomes from -40 to -30 ° C. To the resulting solution is added dropwise a solution of 4.02 g (19.1 mmol) of 8-acetoxy-2,6-dimethyl-2 (E), 6 (E) -octadiene-1-al (2- 1) in 10 ml of toluene.

After the addition, the mixture is stirred vigorously at said temperature for 2 hours. A 10% aqueous solution of 35 hydrochloric acid is added to the reaction mixture and the toluene layer is separated.

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DK 171415 B1 20 reads from. The toluene layer is washed with water and then with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The toluene is evaporated from the toluene layer and the residue chromatographed on a silica gel column using an eluent composed of a 7: 3 mixture by volume of hexane and ethyl acetate to give 8.46 g of a colorless transparent oil. From the following analytical data, this product has been determined to be a mixture of diastereomers of 1-acetoxy-8-hydroxy-3,7-10-dimethyl-9- (2,6,6-trimethyl-1-cyclohexene-1 -yl) -9-phenylsulfonyl-2 (E), 6 (E) -nonadiene (3) · Yield 91%.

CDCl3 NMR 6 (CH3T3SiOSi (CH3) 2: 0.61-2.03 (m, 28H); 2.87 (br, 1H); 3.95, 4.20 (d, 1H total); 50 (d, 2H); 4.85, 4.97 (d, 1H total); 5.25, 5.62 (m, 2H total); 7.40-8.03 (m, 5H).

IR (film) (cm -1): 3500 (OH), 1735 (C = O), 1140 (SO 2). FD MASS m / e: 488 (M +).

20 ίΒ1 o o = s = o OAC; In a 100 ml flask, 2.67 g (5.5 mmol) of compound (3) and 9.65 ml (110 mmol) of methylal are charged and the mixture is stirred to form a solution . To this solution is added 0.22 g (1.54 mmol) of phosphorus pentoxide, and DK 171415 B1 21

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the mixture is stirred at room temperature. Respectively. Two hours and five hours later, 0.21 g of phosphorus pentoxide is added and the reaction is carried out for 24 hours.

A saturated aqueous solution of sodium bicarbonate 5 is charged into a separatory funnel and the solution portion of the reaction mixture is added thereto. Toluene and a saturated aqueous solution of sodium bicarbonate are added to the residue and the mixture is stirred to dissolve the tar-like material. The resulting aqueous layer and organic layer are transferred to the separating funnel. The separated organic layer is washed with a saturated aqueous solution of sodium bicarbonate and dried over anhydrous magnesium sulfate.

Anhydrous magnesium sulfate is removed by filtration and the solvent is evaporated at 40 ° C to give a red, oily product. The oily product is chromatographed on a silica gel column using an eluant consisting of a mixture of ethyl acetate and n-hexane in a ratio of from 1: 6 to 1: 4 to give 2.68 g of a yellow oil. From the following 20 analytical data, this product has been determined to be 1-acetoxy-3,7-dimethyl-8-methoxymethoxy-9-phenylsulfonyl-9- (2,6,6-trimethyl-1-cyclohexene). 1-yl) -2 (E), 6 (E) -nonadiene (_4). yield 92%.

> · Η, CDCl, NMRrf (CH 3? 3 SiOSi (CH 3) 3: 0.69-1.99 (m, 28H); 3.16, 3.35 (s, 3H); 3.96-5 , 60 (m, 8H); 7.38-8.01 (m, 5H).

IR (film) O (cm -1): 1730 (C = O), 1140 (SO 2

FD MASS m / e: 532 (M +).

In a 100 ml flask, 2.68 g of the compound 15 (4) and 11 ml of methanol are charged, and the mixture is stirred to form a solution. 0.33 g of sodium hydroxide is added and the mixture is stirred at room temperature for 1.5 hours. The reaction mixture is transferred to a separatory funnel and a large amount of water and toluene is added to extract the mixture 20 with toluene. The toluene extract is washed with a saturated aqueous solution of ammonium chloride and water and dried over anhydrous magnesium sulfate. Anhydrous magnesium sulfate is removed by filtration and the toluene is evaporated at 40 ° C under reduced pressure to give a red, oily product.

The oily product is chromatographed on a silica gel column using an eluant composed of a mixture of ethyl acetate and n-hexane in a ratio of from 1: 1 to 1: 4 to give 2.34 g of a yellow oil.

From the following analytical data, this product has been determined to be 1-hydroxy-3,7-dimethyl-8-methoxymethoxy-9-phenylsulfonyl-9- (2,6,6-trimethyl-1-cyclohexene 1-yl) -2 (E), 6 (E) -nonadiene (J5).

35

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NMR (CH 3 T 3 SiOSi (CH 3) 3 δ 0.68-2.04 (m, 26H); 3.15, 3.36 (s, 3H); 3.95-5.60 (in, 8.40-8.00 (m, 5H).

IR (film) v (cm ”1) in 3500 (OO), 1140 (SO₂).

(D) Q

o = s = o 10 COME ^ 5 AC2 ° ^ 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 2

Under an atmosphere of nitrogen gas, 0.5121 g (1.05 mmol) of the compound (5) 4 and 5 ml of toluene are charged to a 350 ml brown flask and the mixture is stirred to form a solution. To the solution is added 0.21 g (3.15 mmol) of potassium methoxide and the mixture is stirred at room temperature for 7 minutes and, further, at 40 ° C for 2 hours.

20 ml of hexane and 15 ml of water are added to the reaction 9 mixture and the mixture is transferred to a separatory funnel.

10

The separated aqueous layers are extracted with 15 ml of hexane and the 11 extracts are combined with the hexane layer. The mixture is washed 2 times 12 g with water and dried over anhydrous magnesium sulfate. Water 13 free magnesium sulfate is removed by filtration and the solvent 14 is evaporated at 35 ° C at reduced pressure to give 15 of an orange, oily product. The IR spectrum of this 16 product is consistent with the spectrum of commercial vitamin A (6J.

DK 171415 B1 24

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Under a nitrogen atmosphere, the oily product prepared above, 4 ml of hexane and 1.1 ml of triethylamine, are charged into a 100 ml brown flask and cooled with an ice-water bath. 0.68 ml of acetic anhydride is added and the mixture is stirred at the same temperature for 20 minutes and additionally at room temperature for 16 hours.

25 ml of hexane is added to the reaction mixture and the mixture is cooled with an ice-water bath. Then add 10 ml of a saturated aqueous solution of sodium bicarbonate. The mixture is stirred for 15 minutes and transferred to a separatory funnel. It is separated by the addition of 15 ml of hexane and 10 ml of a saturated aqueous solution of sodium bicarbonate. The hexane layer is washed with a saturated aqueous solution of sodium bicarbonate and dried over anhydrous magnesium sulfate.

Anhydrous magnesium sulfate is removed by filtration and the solvent is evaporated at 35 ° C under reduced pressure to give 0.3723 g of an orange, oily product. In high performance liquid chromatography (column: μ-porasil, mobile phase: a 9: 1 mixture of hexane and diisopropyl ether), the oily product is found to contain 0.2755 g (trans compound content only: 95% ) vitamin A acetate (2). The total yield based on the compound (J5) is 80%.

EXAMPLE 2 (A) 30 ^ T ° n-BuLl) --1_>. - £ -) 9 DK 171415 B1 25

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In a 200 ml flask flushed with argon gas, fill 5.00 g (18.0 mmol) of beta-cyclogeranyphenyl sulfone (1_) and 60 ml of tetrahydrofuran and cool to -78 ° C. Then 6.6 ml (9.9 mmol) of a hexane solution of n-butyllithium (1.5 mol / liter) is added dropwise and the mixture is stirred at the above temperature for 3 hours. Then a solution of 1.89 g (9.0 mmol) of 8-acetoxy-2,6-dimethyl-2 (E), 6 (E) -octadiene-1-al (2-1) in 15 ml is added. tetrahydrofuran dropwise at -78 ° C and the mixture is stirred at this temperature for 2 hours and furthermore at -50 ° C for 2 hours. The reaction mixture is cooled to -78 ° C and water is added thereto. Then the mixture is raised to room temperature. The mixture is extracted with three 100 ml portions of benzene. The extracts are washed with water and dried under anhydrous sodium sulfate. The benzene is evaporated from the extracts and the residue is chromatographed on a silica gel column using an eluant composed of a 5: 1 volume by volume of hexane and ethyl acetate to give 4.01 g of a colorless transparent oil. From the following analytical data, the product has been determined to be 1-acetoxy-8-hydroxy-3,7-dimethyl-9 - (2,6,6-trimethyl-1-cyclohexen-1-yl) -9 -phenylsulfonyl - 2 (E), 6 (E) -nonadiene (_3). Yield 93%.

NMR (CH 3 T 3 SiOSi (CH 3) 3: 0.62-1.94 (m, 28H); 3.73 (br, 1H); 3.81 (d, 1H); 4.41 (d, 2H); 4.90 (d, 1H); 5.21 (m, 2H); 7.38-7.99 (m, 5H).

IR (film) vicnf1): 3500 (OH), 1735 (C * 0), 1140 (SO2).

FD MASS m / e: 488 (M +).

35 DK 171415 B1 26 o (B)

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0 = S = 0 kA Lh 3 P ^ TsOH>

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In a 100 ml flask, 1.36 g (2.8 mmol) of 1-acetoxy-3,7-dimethyl-8-hydroxy-9-phenylsulfonyl is charged into a 100 ml flask. -9- (2,6,6 - trimethyl-1-cyclohexen-1-yl) -2 (E), 6 (E) -nonadiene (, 3), a catalytic amount of pyridinium p-toluenesulfonate and 15 ml methylene chloride and cooled with an ice-water bath. To the solution is added dropwise 0.73 ml (8.4 mmol) of 3,4-dihydro-2H-pyran and the mixture is stirred for 3 hours with cooling in the bath. An aqueous sodium bicarbonate solution is poured into the reaction mixture and the mixture is extracted with 30 methylene chloride. The methylene chloride extract is washed with water and dried over anhydrous sodium sulfate. Methylene chloride is evaporated from the extract by an evaporator and the residual oil is chromatographed on a silica gel column using an eluent composed of a 1: 5 mixture of ethyl acetate and n-hexane to give 1.59 g of 1-acetoxy-3,7-dimethyl-8- (tetrahydropyran-2

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(17-yl) -oxy-9-phenylsulfonyl-9- (2,6,6-trimethyl-1-cyclohexen-1-yl) -2 (E), 6 (E) -nonadiene (J3). Yield 99%. The analytical data of the product are as follows: cdCl 3 NMR <* (CH3) 3 SiOSi (CH3) 3: 0.62-2.03 (m, 34H); 3.23-5.36 (m, 9H); 7.43-8.15 (m, 5H).

IR (film)> 2 (cm -1): 1150 (SO2).

FD MASS m / e: 573 (M + +1), 572 (M +).

Under a nitrogen gas atmosphere, 1.59 g of the compound (8) and 15.9 ml of toluene are charged into a 100 ml brown flask and the mixture is stirred to obtain a solution. While maintaining the temperature within the mixture at 27 ° C, 0.97 g of potassium methoxide is added. The mixture is stirred at this temperature for 0.3 hours and then at a temperature in the mixture of 38 ° C for 1.5 hours.

60 ml of hexane and 45 ml of water are added to the reaction mixture and the hexane layer is separated by means of a separating funnel. The aqueous layer is extracted with 45 ml of hexane and the extract is combined with the separated hexane layer. The mixture is washed twice with water and dried over anhydrous magnesium sulfate. Anhydrous magnesium sulfate is removed by filtration and the solvent is evaporated at 35 ° C at reduced pressure to give an orange, oily product (6).

Under a nitrogen gas atmosphere, fill in the above oily product (6), 10.6 ml hexane and 2.9 ml triethylamine in a 100 ml brown flask and cool with an ice-water bath. 1.8 ml of acetic anhydride are added, and the mixture is stirred at the same temperature for 20 minutes and further at room temperature for 16 hours.

70 ml of hexane is added to the reaction mixture and the mixture is cooled with an ice-water bath. To the mixture is added 27 ml of a saturated aqueous solution of sodium bicarbonate and the mixture is stirred for 15 minutes. Reaktionsbian-

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The mixture is transferred to a separatory funnel and separated by the addition of 40 ml of hexane and 27 ml of a saturated aqueous solution of sodium bicarbonate. The hexane layer is washed with a saturated aqueous solution of sodium bicarbonate and dried over anhydrous magnesium sulfate.

Anhydrous magnesium sulfate is removed by filtration and the solvent is evaporated at 35 ° C at reduced pressure to give an orange, oily product. In high performance liquid chromatography (column: μ-porasil, 10 mobile phase: a 9: 1 mixture of hexane and diisopropyl ether) this product is found to contain 0.70 g (content of trans-compound only: 95%) of vitamin A acetate (2) · The yield of the product based on the compound (S) is 77%.

EXAMPLE 3

Q

· - *% 30 Under a nitrogen gas atmosphere, 2.68 g of 1-acetoxy-3,7-dimethyl-8-methoxy-methoxy-9-phenylsulfonyl-9- (2,6,6-trimethyl) flask is charged to a 100 ml brown flask. -1-cyclohexen-1-yl) -2 (E), 6 (E) -nonadiene (4), prepared in Example 1 (B), and 80 ml of cyclohexane, and the mixture is stirred to form a resolution. Then 3.53 g of potassium methoxide is added and the mixture is stirred at a temperature of the mixture at 39 ° C for 1.8 hours.

DK 171415 B1 29

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96 ml of hexane and 72 ml of water are added to the reaction mixture and the mixture is transferred to a separatory funnel. The separated aqueous layer is extracted with 96 ml of hexane and the extract is combined with the separated hexane layer. The mixture 5 is washed twice with water and then dried over anhydrous magnesium sulfate. Anhydrous magnesium sulfate is removed by filtration and the solvent is evaporated at 35 ° C at reduced pressure to give an orange, oily product.

Under a nitrogen gas atmosphere, the aforementioned oily product, 19.2 ml of hexane and 5.3 ml of triethylamine are charged into a 300 ml brown flask and cooled with an ice-water bath. 3.26 ml of acetic anhydride are added and the mixture is stirred at this temperature for 20 minutes and then at room temperature for 16 hours. 120 ml of hexane is added to the reaction mixture and the mixture is cooled with an ice-water bath. Then 48 ml of a saturated aqueous solution of sodium bicarbonate is added and the mixture is stirred for 15 minutes. Then the mixture is transferred to a separatory funnel, 20 and 72 ml of hexane and 48 ml of an aqueous sodium bicarbonate solution are added to separate the mixture into layers. The hexane layer is washed with a saturated aqueous solution of sodium bicarbonate and dried over anhydrous magnesium sulfate.

The magnesium sulfate is removed by filtration and the solvent is evaporated at 35 ° C at reduced pressure to give an orange, oily product. For high performance liquid chromatography (column: μ-porasil, mobile phase: a 9: 1 mixture of hexane and diisopropyl ether), this product is found to contain 1.29 g (content of trans compound only: 95% ) vitamin A-acetate Γ7) · The yield of the product based on the compound (_4) is 78%.

35

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Example 17 (A). rlrl-Q: 9

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10 0 = S = 0 | .

H 2 °.

In a 200 ml three-neck flask flushed with argon gas, 7.01 g (24.0 mmol) of beta-cyclogeranyl-p-tolylsulfone and 70 ml of tetrahydrofuran are charged and cooled to -78 ° C. Then, 9.6 ml (14.4 mmol) of a hexane solution of n-butyllithium (1.5 mol / liter) is added dropwise and the mixture is stirred at the above temperature for 2 hours.

A solution of 2.52 g (12.0 mmol) of 8-acetoxy-2,6-dimethyl-2 (E), 6 (E) -octadien-1-al (2-1) in 15 ml of tetrahydrofuran is added dropwise to the solution at -78 ° C and the mixture is stirred at this temperature for 3 hours. Water is added to the reaction mixture and the temperature of the mixture is raised to room temperature. The mixture is extracted successively with three 50 ml portions of benzene. The benzene extracts are washed with water and dried over anhydrous magnesium sulfate. The solvent is evaporated from the extracts and the residue is chromatographed on a silica gel column using an eluent composed of a mixture of hexane and ethyl acetate in a volume ratio of 5: 1 to 3: 1 to give 4.88 g of a white solid. fabric. From the following analytical data, this product has been determined to be 1-acetoxy-35-8-hydroxy-3,7-dimethyl-9- (2,6,6-trimethyl-1-cyclohexen-1-yl) -9- (p-tolyl) sulfonyl-2 (E), 6 (E) -nonadiene (10). Yield 81%.

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DK 171415 B1 31 NMR δ H 3 O 3 SiOSi (CH 3) δ: 0.61-2.01 (m, 28H); 2.37 (s, 3H); 3.71 (br, 1H); 3.94 (d, 1H); 4.49 (d, 2H); 4.97 (d, 1H); 5.16 (m, 2H); 7.26 (d, 2H); 7.86 (d, 2H).

IR (film) ν (cm ”*): 3480 (OH), 1735 (OO), 1140 (SO₂).

(B) 15 ø

0 = S = 0 I

0AC

Into a 100 ml flask are charged 1.00 g (1.99 mmol) of the compound (1J), 0.52 ml 3,4-dihydro-2H-pyran, 10 ml methylene chloride and a catalytic amount of p-toluenesulfone. acid and the mixture is stirred at 0 ° C for 6 hours.

A saturated aqueous solution of sodium bicarbonate is charged to a separatory funnel and the solution portion of the reaction mixture is added thereto. The methylene chloride layer is separated.

The aqueous layer is extracted with methylene chloride and the extract is combined with the separated methylene chloride layer. The mixture is washed with water and dried over anhydrous magnesium sulfate.

The magnesium sulfate is removed by filtration and the methylene chloride is evaporated by means of an evaporator to give 1.47 g of a viscous oil. The oil is chromatographed on a silica gel column using an eluent composed of a 1: 3 mixture of ethyl acetate and hexane to give 1.09 g of a product. By IR analysis, this product has been determined to be 1-acetoxy-3,7-dimethyl-8- (tetrahydropyran-2-yl) -oxy-9- (p-tolyl) sulfonyl-9- (2,6,6-trimethyl-1-cyclohexen-1-yl) -2 (E), 6 (E) -nonadiene (1 JL). Yield 93%.

IR (film) v (cm: 2930, 1740, 1600, 1450, 1380, 1365, 1300, 1230, 1140, 1080, 1020, 960, 815.

(C) CH, 0 15 0 = S = 0 | KQHe ^

Uk J.O.

0 l of 20 Ac2 ° v Vitamin A pyridine acetate In a 100 ml brown flask, 0.60 g (8.53 mmol) of potassium methoxide and 25 ml of toluene are charged and a solution of 1.00 is added in an argon atmosphere. g (1.71 mmol) of the compound (11) in 5 ml of toluene at room temperature. The mixture is stirred at room temperature for 30 minutes and additionally at 40 ° C for 2 hours.

The reaction mixture is poured into an aqueous solution of ammonium chloride and extracted with diethyl ether.

The extract is washed with water and then with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The magnesium sulfate is removed by filtration and then the diethyl ether and toluene are evaporated to give 0.76 g of a reddish yellow oil (6).

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DK 171415 B1 33

The oil is dissolved in 5 ml of pyridine and 5 ml of acetic anhydride and a catalytic amount of dimethylaminopyridine are added. The mixture is stirred at room temperature for 2 hours.

The reaction mixture is poured into a large amount of water and extracted with n-hexane. The hexane extract is washed with an 80% aqueous solution of methanol and an additional 3 times with water and dried over anhydrous magnesium sulfate. Anhydrous magnesium sulfate is removed by filtration and evaporated n - hexane to give 0.64 g of a reddish yellow oil. By liquid chromatography, this oil is found to contain 0.34 g (content of trans compound only: 95%) of vitamin A acetate. The total yield of the product based on the compound (11) is 61%.

EXAMPLES 5-7 0 o = s = o.

Catalyst 0 = S = 0.11-14 1.36 g (2.8 mmol) of 1-acetoxy-3,7-dimethyl-8-hydroxy-30 -9-phenylsulfonyl-9- (2, 6,6-trimethyl-1-cyclohexen-1-yl) -2 (E), 6 (E) nonadiene (3.), prepared according to Example 2, in 15 ml of methylene chloride is subjected to the following reaction conditions and the reaction mixture is worked up at the same method as in Example 2 to obtain the corresponding aces. The results are shown in the following table.

DK 171415 B1 34 —C ---

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EXAMPLES 8-10

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5 o = s = o OCC ^ '- = * ♦ 15

The same reaction as in Example 1 was carried out under the conditions shown in the table below using 1.05 mmol of each of the compounds (12), (13) and (.14) prepared in Examples 5-7. , for the achievement of vitamin A acetate (2) · The results are shown in the following table.

25 30 35 DK 171415 B1 36 iw i (O C I <#>

0) ti) I w Ό M C C

r — I M (O · Ή ir »1 / ¾ 1 / ¾

O 3 Μ Λ Φ £ S S

£ H +1 M ti Ό Φ O Ή C Ό O W o M 3 Ό I O______

(C

M-l I M IC <Ή <2 5+! £ * 1 æ «· m

SgJS ^ I ^ r> eo> i 3 Φ 4J X., Λ + JUOh Ό · Η (C -P 'P> I ^ _____ Ή Ή · Η -Η μ µ U Φ U CD ο U Φ U Φ ι n ο εο ε χί ο εο ε W 3 h Ή CO · Η μ LD · σ σι · Η GP <N +) fn + J c ^ + jn + j

Ο (0 Ό Q

• Η H · ρ4 ΌΠΌιΛ fl fVO ΙΛ 4J Q) + J φ «. φ ·. <U · »α> -

Αί0 <1> Ο> --Η> 0> rH

«Ε Λ ^ _ ν ® θ '> Η <Ν ιΗ <Ν 0π · Ρ Ο _____________

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Φ ^ ο r ~ r ~ 3Η · · η £ νο m '«r Ο --Εη ο Ό Λ I · Η W 0 ο Ο ε χ ο ·. · 3 Ο Ή m m tn rl £ H Ή 4-> Ο ίο φ ε «ε - c • Η Φ <ΝI ml *» |

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EXAMPLE 11 0.76 g of the reddish yellow oil (6J prepared by reaction of the compound (JL1) with potassium methoxide in toluene in Example 4) is dissolved in 5 ml of pyridine, 5 and the solution is cooled with ice water Then 0.71 g (2.58 mmol) of palmitoyl chloride is added to the solution and the mixture is stirred at the same temperature for 0.5 hour and further at room temperature for 5 hours.

The reaction mixture is poured into a large amount of water 10 and extracted with n-hexane. The hexane extract is washed 3 times with water and dried over anhydrous magnesium sulfate. The magnesium sulfate is removed by filtration and the hexane is evaporated at reduced pressure to give 0.73 g of a reddish yellow oil. By liquid chromatography (column: μ-porasil, mo-15 car phase: a 2: 98 mixture of diisopropyl ether and hexane), this oil is found to contain 0.55 g (content of trans-compound only: 95%) of vitamin A palmitate.

EXAMPLE 12 (A).

Q

In a 100 ml flask, 7.38 g (15 mmol) of 1-ace-toxy-8-hydroxy-3,7-dimethyl-9- (2) are charged to a 100 ml flask. , 6,6-trimethyl-1-cyclohexen-1-yl) -9-phenylsulfonyl-2 (E), 6 (E) -nonadiene (3.),

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positioned according to Example 1 (A), 60 ml of benzene and 12 ml of pyridine, and while the flask is cooled on an ice-water bath, 1.32 ml of thionyl chloride is added dropwise. Then the mixture is stirred at room temperature for 16 hours. A 3% aqueous solution of sulfuric acid cooled with ice is added to the reaction mixture and the organic layer is separated. The aqueous layer is extracted with two 70 ml portions of diethyl ether. The extracts are combined with the organic layer and the mixture is successively washed with a 3% aqueous sulfuric acid solution cooled with ice, a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent is evaporated from the organic layer. The residue is chromatographed on a silica gel column using an eluent 15 composed of a 5: 1 volume by volume of hexane and ethyl acetate to give 7.18 g of a white waxy product. From the following analytical data, this product has been determined to be 1-acetoxy-6-chloro-3,7-dimethyl-9- (2,6,6-trimethyl-1-cyclohexen-1-yl) -9 -20-phenylsulfonyl-2,7-nonadiene (1_5). Yield 94%.

NMR δ <CH3? 3 SiOSi (CH3) 3: 0.72-2.05 (m, 28H)? 4.17-4.57 (m, 4H)? 5.23 (t, 1H); 5.88 (m, 1H); 7.35-7.91 (m, 5H).

IR (film) v (cm -1): 1745 (OO), 1150 (SO2), 685 (C6H5) * FD-MASS m / e: 506 (M +), 507 (M ++ l) to 470 ( M + -HC1), 365 (M + -C6H5SO2).

30 35

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DK 171415 B1 39 (B)

Q

o = s = o 5 KOH ^ p 16 In a 10 ml flask, 0.0226 g (0.342 mmol) of potassium hydroxide is charged with a purity of 85% and 1 ml of methanol. The mixture is stirred at room temperature to prepare a methanol solution of potassium hydroxide. To the solution is added a solution of 0.0373 g (0.0736 mmol) of 1-acetoxy-6-20-chloro-3,7-dimethyl-9- (2,6,6-trimethyl-1-cyclohexene-1- yl) -9-phenylsulfonyl-2,7-nonadiene (1) in a mixture of 2 ml of methanol and 0.2 ml of benzene. The mixture is stirred in an ice-water bath for 30 minutes. A saturated aqueous solution of ammonium chloride is added to the reaction mixture and the solvent is evaporated therefrom. Water is added to the residue followed by extraction with diethyl ether. The extract is washed with a saturated aqueous solution of ammonium chloride and dried over anhydrous magnesium sulfate. The solvent is evaporated from the extract to give 0.0297 g of a 30 yellow oil. From the following analytical data, this product has been identified as 6-chloro-1-hydroxy-3,7-dimethyl-9- (2,6,6-trimethyl-1-cyclohexen-1-yl) -9- phenylsulfonyl-2,7-nonadiene (16). Yield 87%.

NMR c cH ^ SiOSKCHCHjl: 0.75-2.20 (m, 26H); 4.06 (d, 2H); 4.21-4.55 0 (m, 2H); 5; 30 (t, 1H); 5.91 (m, 1H); 7.36-7.90 (m, 5H).

IR (film) ν (cm ”1): 3300 (OH), 1150 (SO₂), 685 (CgHg).

, FD-MASS m / e: 465 (M + +1), 428 (M + -HCl), 323 (M + -C.HcSO-).

5 6 5 2 EXAMPLE 13 0 10 0 = S = 0 Κ13;

Q

To a 50 ml flask, 2.44 g (5.00 mmol) of 1-acetoxy-8-hydroxy-3,7-dimethyl-9- (2,6,6-trimethyl-1 1- cyclohexen-1-yl) -9-phenylsulfonyl-2 (E), 6 (E) -nonadiene (3), 0.12 g of pyridine and 20 ml of methylene chloride. While the flask is cooled with an ice-water bath, 0.29 ml (3.3 mmol) of phosphorus trichloride is added dropwise. Then the mixture is stirred at the above temperature for 6 hours. To the reaction mixture is added a saturated aqueous solution of sodium bicarbonate and the mixture is extracted with diethyl ether.

The extract is washed with a saturated aqueous solution of sodium bicarbonate and dried over anhydrous magnesium sulfate. The solvent is evaporated from the extract and the residue is chromatographed on a silica gel column using an eluent composed of a mixture of hexane 35 and ethyl acetate in a volume ratio of 9: 1 to 5: 1 to give 1.27 g (yield 50%) 1 acetoxy-6-chloro-3,7-

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DK 171415 B1 41-Dimethyl 1-9- (2,6,6-trimethyl-1-cyclohexen-1-yl) -9-phenylsulfonyl-2,7-nonadiene (15) ♦ EXAMPLE 14

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o = s = o PBr3 ^ 10 * 0 ^ OH 30 o = s = o 17 Into a 50 ml flask is charged 2.44 g (5.0 mmol) of 1-20 -acetoxy-8-hydroxy-3.7- dimethyl-9- (2,6,6-trimethyl-1-cyclohexen-1-yl) -9-phenylsulfonyl-2 (E), 6 (E) -nonadiene (2), prepared according to Example 2 (A), 0.12 g of pyridine and 20 ml of methylene chloride, and while the flask is cooled with an ice-water bath, add 0.31 ml (3.3 mmol) of phosphorus tribromide 25 dropwise and the mixture is stirred at this temperature for 1.5 hours. To the reaction mixture is added a saturated aqueous solution of sodium bicarbonate followed by extraction with diethyl ether. The extract is washed successively with a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent is evaporated from the extract and the residue chromatographed on a silica gel column using an eluent composed of a mixture of hexane and ethyl acetate in a volume ratio of 9: 1 to 3: 1 to give 2.34 g of white, waxy product. From the following analysis,

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In this data, this product has been determined to be 1- acetoxy-6-bromo-3,7-dimethyl-9- (2,6,6-trimethyl-1-cyclohexen-1-yl) -9-phenylsulfonyl-2,7-nonadiene (1/7). Yield 85%.

Δ NMR δ δ (Λϋ x (CH 2 TjSxOSi (CH 2) 2: 1.71-2.03 (m, 28H); 4.32-4.57 (m, 4H); 5.24 (m , 1H); 5.90 (m, 1H); 7.43-7.90 (m, 5H).

IR (film) vicm'1): 1730 (C = O), 1135 (SO2), 670 (C6 H5) * FD-MASS m / e: 550 (M +), 470 (M + -HBr), 409 (m + -c6h5so2).

EXAMPLE 15 (A),

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o = s = o.

20 s ° cl2 ^ Φ 25 0 = S = 0

OAC

To a 50 ml flask is charged 610 mg (1.26 mmol) of 1- acetoxy-8-hydroxy-3,7-dimethyl-9- (2,6,6-trimethyl-1-cyclohexen-1-yl) ) -9- (p-tolyl) sulfonyl-2 (E), 6 (E) -nona-diene (10), prepared according to Example 4 (A), 0.96 ml (12 mmol) of pyridine and 15 ml of benzene . While the flask is cooled with an ice-water bath, 0.11 ml (1.5 mmol) of thionyl chloride is added and the mixture is stirred at room temperature for 16 hours. The reaction mixture is partitioned between 1N hydrochloric acid and

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Benzene, the organic layer is washed with water and dried over anhydrous magnesium sulfate and the solvent is evaporated to give 630 g of a yellow oil. From the following analytical data, this product has been determined to be 1-acetoxy-6-chloro-3,7-dimethyl-9- (2,6,6-trimethyl-1-cyclohexen-1-yl) -9 - (p-tolyl) -sulfonyl-2,7-nonadiene (18). It has been found from NMR analysis that the oily product has a purity of 89%. Yield 88%.

NMR δ (CH 3? 3 SiOSi (CH 3) 3: 0.70-1.93 (m, 28H); 2.40 (s, 3H); 4.15-4.43 (m, 4H); 5.17 (t, 1H); 5.82 (d, 1H); 7.21 (d, 2H); 7.64 (d, 2H).

IR (film) ν (cm -1): 1740 (C = O), 1150 (SO

EXAMPLE 16 20 0 o = s = 0 COME Ac2 ° A 50 ml flask flushed with argon gas was charged 0.4951 g (0.977 mmol) of 1-acetoxy-6-chloro-3,7-dimethyl 9- (2,6,6-trimethyl-1-cyclohexen-1-yl) -9-phenylsulfonyl-2,7-nonadiene (15) and 15 ml of cyclohexane. After the mixture has been stirred for a while, 0.70 g (10 mmol) of potassium methoxide is added and the mixture is stirred at 38 ° C for 2 hours. To the reaction mixture is added 30 ml of diisopropyl ether and 15 ml of a saturated aqueous solution of ammonium chloride. The organic layers are separated and the aqueous layer DK 171415 B1 44

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extract with 20 ml of diisopropyl ether. The extract is combined with the organic layer and the mixture is washed with a saturated aqueous solution of ammonium chloride and dried over anhydrous magnesium sulfate. The organic solvent is evaporated from the organic layer and the residue is filled with 4 ml of a 0.05% by weight solution of 2,6-di-t-butyl-4-methylphenol in hexane and 1.1 ml of triethylamine in a 100 ml flask flushed with argon. During ice-base cooling, 0.68 ml of acetic anhydride is added to the mixture, and the mixture is stirred for one day at room temperature. To the reaction mixture is added 50 ml of hexane and 10 ml of saturated aqueous sodium bicarbonate solution. The mixture is stirred for a while and the hexane layer is separated. The hexane layer is washed with a saturated aqueous solution of sodium bicarbonate and dried over anhydrous magnesium sulfate. Evaporation of hexane from the hexane layer gives 0.3462 g of a red oil. FD - MASS analysis of this oily product shows a peak at m / e = 328. This leads to the determination that the main component of the oily product is vitamin A acetate 20 (I) -

Subsequently, the vitamin A acetate is quantified by high performance liquid chromatography using methyl stearate as the internal standard. As a result, the yield of vitamin A acetate is found to be 70%, based on 1-acetoxy-6-chloro-3,7-dimethyl-9- (2,6,6-trimethyl-1-cyclohexene) (1-yl) -9-phenylsulfonyl-2,7-nonadiene (_15) and the content of the trans compound only is 93%.

EXAMPLE 17 o = s = o

KOHe J AC2 ° J

35

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DK 171415 B1 45

The same reaction separation operations are performed as in Example 16 except that 0.5538 g (1.01 mmol) of 1-acetoxy-6-bromo-3,7-diroethyl-9- (2,6,6-) is used. trimethyl-1-cyclohexen-1-yl) -9-phenylsulfonyl-2,7-nonadiene 5 (17), prepared according to Example 14, instead of 0.4951 g (0.977 mmol) of 1-acetoxy-6-chloro-3 7-Dimethyl-9- (2,6,6-trimethyl-1-cyclohexen-1-yl) -9-phenylsulfonyl-2,7-nonadiene, and a mixture of 10 ml of cyclohexene and 5 ml of toluene is used. instead of 15 ml of cyclohexane. As a result, 0.3195 g of a red oily product is obtained. FD-MASS analysis of the oily product shows a peak at m / e = 328, which leads to the determination that the main component of the oily product is vitamin A acetate (2) ·

The resulting vitamin A acetate is quantified by high performance liquid chromatography in the same manner as in Example 16. It turns out that the yield of vitamin A - acetate is 70% based on 1-acetoxy-6-bromo-3.7 -dimethyl-9- (2,6,6-trimethyl-1-cyclohexen-1-yl) -9-phenylsulfonyl-2,7-nonadiene (17) and the content of the trans-20 compound alone is 93 %.

EXAMPLE 18 (A)

.. Q

o = s = o.

COME 16 16 In a 10 ml flask flushed with argon gas, 0.0232 g (0.050 mmol) of 6-chloro-1-hydroxy-3,7-dimethyl-9- (2,6,6-trimethyl-1- cyclohexen-1-yl) -9-phenylsulfonyl-2,7-nonadiene (16), prepared according to Example 12 (B), DK 171415 B1 46

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and 5 ml of cyclohexane, and then 0.0352 g (0.50 mmol) of potassium methoxide is added. The mixture is stirred at 35 ° C for 2 hours. The reaction mixture is added to a mixture of 20 ml of diisopropyl ether and 10 ml of a saturated aqueous solution of ammonium chloride. The organic layers are separated, dried over anhydrous magnesium sulfate and concentrated to ca. 1 ml. FD - MASS analysis of the concentrate shows a peak at m / e = 286. This leads to the determination that the concentrate contains vitamin A (j6).

(B) C15H31 ^ C1 j

The above concentrate is dissolved in 2 ml of pyridine and the solution is cooled with an ice-water bath. Then 0.0137 g (0.05 mmol) of palmitoyl chloride is added to the solution and the mixture is stirred under ice-bath cooling for 0.5 hour and then at room temperature for 5 hours. The reaction mixture is poured into a large amount of water and extracted with hexane.

The hexane extract is washed with water and dried over anhydrous magnesium sulfate. The magnesium sulfate is removed by filtration and hexane is evaporated from the filtrate at reduced pressure. As a result, 0.0282 g of a reddish yellow oil is obtained. The oil is determined by liquid chromatography (column: μ-porasil, mobile phase: a 2: 98 mixture by volume of diisopropyl ether and hexane) to contain 0.0183 g of vitamin A palmitate.

35 DK 171415 B1 47

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EXAMPLE 19

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OAc KOMe ^ Ac2 ° ^

Cl is

The same reaction and separation operations as in Example 17 are performed except that 0.5127 g (0.985 mmol) of 1-acetoxy-6-chloro-3,7-dimethyl-9- (2,6,6-trimethyl) is used. -1-cyclohexen-1-yl) -9- (p-tolyl) -sulfonyl-2,7-nonadiene (JL8) instead of 0.5538 g (1.01 mmol) of 1-acetoxy-6-bromo -3,7-dimethyl-9- (2,6,6-trimethyl-l-cyclo-hexene-l-yl) -9-phenylsulfonyl-2,7-nonadiene. As a result, 0.3325 g of a red oily product is obtained. FD-MASS - analysis of the oily product shows a peak at m / e = 328. This leads to the determination that the main component of the oily product is vitamin A acetate. Then, in the same way as in Example 16, the vitamin A acetate reducing agent is quantified by high performance liquid chromatography. It turns out that the yield of vitamin A acetate (2) is 68%, based on 1-acetoxy-6-chloro-3,7-dimethyl-9- (2,6,6-trimethyl-1-cyclohexene). 1-yl) -9- (p-tolyl) -sulfonyl-2,7-nonadiene (18) and that the content of the trans-compound alone is 93%.

EXAMPLE 20 DK 171415 B1 48

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Q

o = s = o 5 n-BuOK J Ac2 ° ^

The same reaction and separation operations as in Example 16 are performed except that 1.12 g (10 mmol) of potassium n-butoxide is used instead of 0.70 g (10 mmol) of potassium methoxide. As a result, 0.3481 g of a red, oily product is obtained. In the same way as in Example 16, the resulting vitamin A acetate is quantified by high performance liquid chromatography. It turns out that the yield of vitamin A acetate (2) is 72% based on 1-acetoxy-6-chloro-20 -3,7-dimethyl-9- (2,6,6-trimethyl-1-cyclohexene) -l-yl) -9- -phenylsulfonyl-2,7-nonadiene (JJ3J ') and the content of the trans-compound alone is 92%.

EXAMPLE 21

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° -f- °.

30 - 1 In a 50 ml flask flushed with argon gas, 0.4913 g (0.970 mmol) of 1-acetoxy-6-chloro-3.7 is charged. -dimethyl-9- (2,6,6-trimethyl-1-cyclohexen-1-yl) -9-phenylsulfonyl-2,7-nonadiene (_15), prepared according to Example 12 (A), DK 171415 B1 49

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and 15 ml of cyclohexane. The mixture is stirred for a while and 0.66 g (10 mmol) of potassium hydroxide (85% purity) is added. The mixture is stirred at 65 ° C for 1.5 hours and, further, at reflux temperature for 2 hours. After cooling, 30 ml of diisopropyl ether and 15 ml of a saturated aqueous solution of ammonium chloride are added to the reaction mixture. The organic layer is separated and the aqueous layer is extracted with 20 ml of diisopropyl ether. The extract is combined with the organic layer and the mixture is washed with a saturated aqueous solution of ammonium chloride and dried over anhydrous magnesium sulfate. The organic solvent is evaporated from the organic layer and the residue is filled with 5 ml of a 0.05% by weight solution of 2,6-di-t-butyl-4-methylphenol in hexane and 1.1 ml of triethylamine in a 100 ml 15 flask flushed with argon. During ice-bath cooling, 0.68 ml of acetic anhydride is added to the mixture. The mixture is stirred at room temperature for 24 hours. To the reaction mixture is added 50 ml of hexane and 10 ml of a saturated aqueous solution of sodium bicarbonate. The mixture is stirred for a while and the hexane layer is separated. The hexane layer is washed with a saturated aqueous solution of sodium bicarbonate and dried under anhydrous magnesium sulfate. Hexane is evaporated from the hexane solution to give 0.3577 g of a red oily product. The resulting vitamin A acetate is quantified by high performance liquid chromatography in the same manner as in Example 16. It turns out that the yield of vitamin A acetate (2) is 64%, based on 1-acetoxy-6-chloro-3 7-Dimethyl-9- (2,6,6-trimethyl-1-cyclohexen-1-yl) -9-phenylsulfonyl-2,7-nonadiene, and the content of the trans-compound alone is 90 %.

35 DK 171415 B1 50

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EXAMPLE 22

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o = s = o 0Ac DBU ^

Cl 5

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10 o = s = o.

In a 50 ml flask, 1.55 g (3.1 mmol) of 1-acetoxy-6-chloro-3,7-dimethyl-9- (2,6,6-trimethyl-1-cyclohexene) is charged. 1-yl) -9-phenylsulfonyl-2,7-nonadiene (L5), prepared according to Example 12 (A), 30 ml of diethyl ether and 0.85 ml (6.0 mmol) of 1,8-diazabicyclo [5, 4,0] undec-7, and the mixture is stirred for 10 hours under reflux. The reaction mixture is partitioned between diethyl ether and water. The ether layer is washed successively with 5% sulfuric acid and a saturated aqueous solution of sodium bicarbonate and dried over anhydrous magnesium sulfate. The solvent is evaporated from the ether solution, and the residue is chromatographed on a silica gel column using an eluent composed of a 3: 1 volume by volume of hexane and ethyl acetate to give 1.23 g of a yellow oily product. From the following analytical data, this product has been determined to be 1-acetoxy-3,7-dimethyl-9- (2,6,6-tri-methyl-1-cyclohexen-1-yl) -9 -phenylsulfonyl-2,6,8-nona-triene (1j)). Yield 86%.

35

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DK171415 B1 51 MMD aCDCI NMR 6 (CH3? 3 SiOSi (CH3) 3: 0.86-2.27 (m, 28H); 4.51 (d, 2H); 5.25 (t, 1H); , 67-5.90 (ro, 1H); 7.14-7.90 (m, 6H).

IR (film) ν (cm ** 1): 1745 (OO), 1150 (SO₂).

FD-MASS xn / e: 470 (M +), 328 (M + -CgH5SO2).

EXAMPLE 23 10 KOH ^ 15 Cl

Q

o = s = o A 100 ml flask is charged with 2,5347 g (5.00 mmol) of 1-acetoxy-6-chloro-3,7-dimethyl-9- (2,6,6-trimethyl-1-cyclohexane). (Hexene-1-yl) -9-phenylsulfonyl-2,7-nonadiene (Γ5), prepared according to Example 12 (A), 6 ml of benzene and 20 ml of methanol, and the mixture is stirred to form a solution. The solution is cooled with an ice-water bath and a solution of 1.35 g (20 mmol) of potassium hydroxide (purity 85%) in 15 ml of methanol is added. The mixture is stirred in the ice-water bath for 5 minutes and further at room temperature for 18 hours. A saturated aqueous solution of ammonium chloride is added to the reaction mixture and the mixture is extracted successively with three 100 ml portions of diethyl ether. The extracts are washed with a saturated aqueous solution of ammonium chloride and dried over anhydrous magnesium sulfate. The solvent is evaporated from ether.

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The solution is chromatographed on a silica gel column using an eluent composed of a mixture of hexane and ethyl acetate in a volume ratio of 4: 1 to 3: 1 to give 1.5071 g of a 5 yellow , oily product. From the following analytical data, the product has been determined to be 1-hydroxy-3,7-dimethyl-9- (2,6,6-trimethyl-1-cyclohexen-1-yl) -9-phenylsulfonyl 2,6,8-nonatriene (£). Yield 70%.

NMR δ <(CH 3? 3 SiOSi (CH 3) 3: 0.90-2.28 (m, 26H); 4.07 (m, 2H); 5.35 (t, 1H); 89 (m, 1H); 7.13-7.90 (m, 6H).

IR (film) V (cm -1): 3450 (OH), 1140 (SO2).

FD MASS m / e: 428 (M +), 287 (M + -C6H5SO2).

EXAMPLE 24

20 O

PBN; 25

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o = s = 0.1 In a 50 ml flask, 1.38 g (2.5 mmol) of 1-acetoxy-6-bromo-3,7-dimethyl-9- (2,6,6-trimethyl-1- cyclohexen-1-yl) -9-phenylsulfonyl-2,7-nonadiene (17), prepared according to Example 14, 15 ml of methylene chloride and 0.6 ml (5 mmol) of 1,5-diazabicyclo [4.3 , 0] non-5-ene. The mixture is stirred in B5 53

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hours under reflux. The reaction mixture is worked up in the same operation as in Example 22 to give 0.99 g (yield 84%) of 1-acetoxy-3,7-dimethyl-9- (2,6,6-trimethyl-1-cyclohexene-1 yl) -9-phenylsulfonyl-2,6,8-nona-triene (19).

Example 25 0 10 o = s = o KOH ^

, 5 Q

o = s = o 20

The same reaction and separation operations as in Example 23 are performed except that 1.36 g (2.5 mmol) of 1-acetoxy-6-bromo-3,7-dimethyl-9- (2,6,6- -trimethyl-1-cyclohexen-1-yl) -9-phenylsulfonyl-2,7-nonadiene (.17), prepared according to Example 14, instead of 2.5347 g (5.00 mmol) of 1-acetoxy -6-chloro-3,7-dimethyl-9- (2,6,6-trimethyl-1-cyclohexen-1-yl) -9-phenylsulfonyl-2,7-nonadiene (1-5). As a result, 0.87 g (yield 73%) of 1-hydroxy-3,7-dimethyl-9- (2,6,6-trimethyl-1-cyclohexen-1-yl) -9-phenylsulfonyl-1 2,6,8-nonatrien.

EXAMPLE 26 54

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(A), ø 5 0 = S = 0 S0C12 ^ kJ OH yes

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10 0 = s = 0

In a 100 ml flask, 4.27 g (8.82 xranol) of 1-acetoxy-8-hydroxy-3,7-dimethyl-9- (2,6,6-trimethyl-1- -cyclohexen-1-yl) -9- (p-tolyl) -sulfonyl-2,6-nonadiene (10J, prepared according to Example 4 (A), 6.7 ml (84 mmol) of pyridine and 50 ml of benzene While the flask is cooled with an ice-water bath, 0.77 ml (11 mmol) of thionyl chloride is added, and then the mixture is stirred at room temperature for 16 hours The reaction mixture is partitioned between 1N hydrochloric acid and benzene.

The organic layer is washed with water and dried over anhydrous magnesium sulfate. The solvent is evaporated to give 4.41 g of a yellow oily product. From the following analytical data, this product has been determined to be 1-acetoxy-6-chloro-3,7-dimethyl-9- (2,6,6 - trimethyl-1-cyclohexen-1-yl) -9 - (p-tolyl) -sulfonyl-2,7-30-nonadiene (18). From NMR analysis, the purity of the oily product has been found to be 89%. Yield 88%.

35 DK 171415 B1 55

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NMR δ <(CH 3? 3 SiOSi (CH 3) 3: 0.70-1.93 (m, 28H); 2.40 (s, 3H); 4.15-4.43 (m, 4H); 5.17 (t, 1H); 5.82 (d, 1H); 7.21 δ (d, 2H); 7.64 (d, 2H).

IR (film) vtcnf1): 1740 (C = O), 1150 (SO2).

(B-l)

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1 ° ° ± 0 I

DBU ^ C1 18 ø 15 o = s = o 21 20 The same reaction and separation operations as in Example 22 are performed except that 1.75 g (3.0 mmol) of 1-acetoxy-6-chloro-3 is used, 7-Dimethyl-9- (2,6,6-trimethyl-1-cyclohexen-1-yl) -9- (p-tolyl) -sulfonyl-2,7-nonadiene U8) (purity 89%) instead for 1.55 g (3.1 mmol) of 1-acetoxy-6-chloro-3,7-dimethyl-9- (2,6,6-trimethyl-1-cyclohexen-1-yl) -9- phenylsulfonyl-2,7-nonadiene (15). As a result, 1.19 g of a yellow oily product is obtained. From the following analytical data, this product has been determined to be 1-acetoxy-3,7-dimethyl-9- (2,6,6-30-trimethyl-1-cyclohexen-1-yl) -9- (p tolyl) -sulfonyl-2,6,8-nonatrien (21). Yield 82%.

35 DK 171415 B1 56

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MMD for CDCl 3 N ″ (CH 3 J 3 SiOSi (CH 3) 3: 0.87–2.25 (in, 28H); 2.40 (s, 3H); 4.51 (d, 2H); 5.24 (t, 1H) 5.66-5.90 (m, 1H); 7.14-7.98 (ro, 5H).

IR (film) ν (cm ”1): 1745 (C = O), 1150 (SO₂).

FD-MASS m / e: 484 (M +), 328 (M + -CH 3 C 6 H 4 SO 2 H).

(B-2) io 0 o = s = o KOH ^ 0 o = s = o 20 µl

The same reaction and separation operations as in Example 23 are performed except that 2.92 g (5.0 mmol) of 1-acetoxy-6-chloro-3,7-dimethyl-9- (2,6,6- 25-trimethyl-1-cyclohexen-1-yl) -9- (p-tolyl) sulfonyl-2,7-nonadiene (1-8) (purity 89%) instead of 2.5347 g (5.00 mmol) 1-Acetoxy-6-chloro-3,7-dimethyl-9- (2,6,6-trimethyl-1-cyclohexen-1-yl) -9-phenylsulfonyl-2,7-nonadiene (JL5).

As a result, 1.45 g of a yellow oil is obtained. From the following 30 analytical data, the oil has been determined to be 1-hydroxy-3,7-dimethyl-9- (2,6,6-trimethyl-1-cyclo-hexen-1-yl) -9- (p -tolyl) -sulfonyl-2,6,8-nonatriene (22). Yield 66%.

35

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NMR (CH 3? 3 SiOSi (CH 3) 3: 0.89-2.27 (m, 26H); 2.40 (s, 3H); 4.06 (m, 2H); 5.33 (t , 1H); 5.67-5.89 (m, 1H); 7.13-7.99 (m, 5H).

IR (film) ν (cm "*): 3450 (OH), 1140 (SO₂).

FD MASS m / e: 442 (M +), 287 (M + -CH 3 C 6 H 4 SO 2).

EXAMPLE 27

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o = s = o 15> OW ^> ^^^^ 0Ac COME ^ AC2 °) 20 * 1 2 3 4 5 6 7 8 9 10 11 In a 50 ml flask flushed with argon gas fill 2 dec 0.4812 g (1 (2 mmol) 1-acetoxy-3,7-dimethyl-9- (2,6,6-3 trimethyl-1-cyclohexen-1-yl) -9-phenylsulfonyl-2,6,8-nona-4-triene ( 1_9), 15 ml of cyclohexane and 0.70 g (10 mmol) of potassium methoxide, and the mixture is stirred at 38 ° C for 2 hours. The reaction mixture is partitioned between 30 ml of diisopropyl ether and 15 ml of a saturated aqueous solution of ammonium chloride. The 8 aqueous layer is extracted with 20 ml of diisopropyl ether and the 9 extract is combined with the organic layer. The mixture is washed 10 with a saturated aqueous solution of ammonium chloride and 11 dried over anhydrous magnesium sulfate. The solvent is removed from the organic layer and the residue is filled up

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With 4 ml of a 0.05% by weight solution of 2,6-di-t-butyl-4-methylphenol in hexane and 1.1 ml of triethylamine in a 100 ml flask flushed with argon gas. To the mixture is added 0.68 ml of acetic anhydride and the whole mixture is stirred at room temperature for one day. The reaction mixture is stirred for a while with 50 ml of hexane and 10 ml of a saturated aqueous solution of sodium bicarbonate and the hexane layer is separated. The hexane layer is washed with a saturated aqueous solution of sodium bicarbonate and dried over anhydrous magnesium sulfate. Hexane is evaporated from the hexane solution to give 0.3276 g of a red oily product. FD - MASS analysis of the oily product shows a peak at m / e = 328. This leads to the determination that the main component of the oily product is vitamin A acetate 15 (2) · The resulting vitamin A acetate is quantified by high performance liquid chromatography using methyl stearate as an internal standard. It is found that the yield of vitamin A acetate is 74%, based on 1-acetoxy-3,7-dimethyl-9- (2,6,6-trimethyl-1-cyclohexen-1-yl) -9- 20-phenylsulfonyl-2,6,8-nonatriene (22) / and the content of the trans-compound alone is 93%.

EXAMPLE 28

26 O

o = s = o

KOMe J

AC2 °)

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DK 171415 B1 59

The same reaction and separation operations as in Example 27 are performed except that 0.4495 g (1.05 mmol) of 1-hydroxy-3,7-dimethyl-9- (2,6,6-trimethyl-1-cyclo) hexen-1-yl) -9-phenylsulfonyl-2,6,8-nonatriene (2-O), prepared according to Example 23, is used instead of 0.4812 g (1.02 mmol) of 1-acetoxy-3, 7-Dimethyl-9- (2,6,6-trimethyl-1-cyclohexen-1-yl) -9-phenylsulfonyl-2,6,8-nonatriene (19j.

As a result, 0.3285 g of a red, oily product is obtained. In the same way as in Example 27, the resulting vitamin A acetate (2) is quantified by high performance liquid chromatography. It turns out that the yield of vitamin A - acetate is 77%, based on 1-hydroxy-3,7-dimethyl-9- (2,6,6-trimethyl-1-cyclohexen-1-yl) -9 -phenylsulfonyl-2,6,8-nonatriene (2J)) and the content of the trans-compound alone is 93%.

Example 29 0 o = s = o COME ^ 25 Ac2Q ^

The same reaction and separation operations as in Example 27 are performed except that 0.5227 g (1.08 mmol) of 1-acetoxy-3,7-dimethyl-9- (2,6,6-tri-methyl) is used. -1-cyclohexen-1-yl) -9- (p-tolyl) -sulfonyl-2,6,8- -nonatriene (21), prepared according to Example 26 (B1), in

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DK 171415 B1 60 instead of 0.4812 g (1.02 mmol) of 1-acetoxy-3,7-dimethyl-9 - (2,6,6-trimethyl-1-cyclohexen-1-yl) -9-phenylsulfonyl --2,6,8-nonatriene (19). As a result, 0.3156 g of a red, oily product is obtained. The resulting vitamin A-5 acetate (7) is quantified by high performance liquid chromatography in the same manner as in Example 27. It is found that the yield of vitamin A acetate is 70% based on 1- acetoxy-3,7- dimethyl-9- (2,6,6-trimethyl-1-cyclohexen-1-yl) -9- (p-tolyl) -sulfonyl-2,6,8-nonatriene (23J), and the content of trans compound is 93%.

EXAMPLE 30 0

KOMe J

20 ÅC20 ^ 25 2

The same reaction and separation operations as in Example 27 are performed except that 0.4464 g (1.01 mmol) of 1-hydroxy-3,7-dimethyl-9- (2,6,6-30-trimethyl-1) is used. -cyclohexen-1-yl) -9- (p-tolyl) -sulfonyl-2,6,8-nonatriene (22), prepared according to Example 26 (B1), instead of 0.4812 g (1.02 mmol) 1-Acetoxy-3,7-dimethyl-9- (2,6,6-trimethyl-1-cyclohexen-1-yl) -9-phenylsulfonyl-2,6,8-nonatriene (, 19). As a result, 0.3201 g of 35 is obtained from a red, oily product. In the same way as in Example 27, the resultant vitamin A acetate (2) is quantified.

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by high performance liquid chromatography. The yield of vitamin A acetate is found to be 74%, based on 1-hydroxy-3,7-dimethyl-9- (2,6,6-trimethyl-1-cyclohexen-1-yl) -9- - (p-tolyl) -sulfonyl-2,6,8-nonatriene (22), and the content of exclusively trans compound is 93%.

EXAMPLE 31 0

10 0 = S = 0I I

n-BuOK ^ s * c2 °) -

The same reaction and separation operations as in Example 27 are performed except that 1.12 g (10 mmol) of potassium n-butoxide is used instead of 0.70 g (10 mmol) of potassium methoxide. As a result 0.3481 g of a red oily product is obtained. Similar to Example 27, the resulting vitamin A acetate (2) is quantified by high performance liquid chromatography. It is found that the yield of vitamin A acetate is 72%, based on 1-acetoxy-3,7-dimethyl-9- (2,6,6-trimethyl-1-cyclohexen-1-yl) -9- 30-phenylsulfonyl-2,6,8-nonatriene (_19) »and that the content of the trans compound is 92% only.

EXAMPLE 32

Q

o = s = o. In a 10 ml flask flushed with argon gas, 0.0235 g (0.050 mmol) of 1-acetoxy-3,7-dimethyl-9- (2,6,6-trimethyl-1) is charged. -cyclohexen-1-yl) -9-phenylsulfonyl-2,6,8-nonatriene (19), prepared according to Example 22, and 5 ml of cyclohexane, after which 0.07 g (1 mmol) of potassium hydroxide (85% purity) added. The mixture is stirred for 2 hours at reflux temperature. The reaction mixture is added to a mixture of 20 ml of diisopropyl ether and 10 ml of a saturated aqueous solution of ammonium chloride. The organic layer 25 is separated, dried over anhydrous magnesium sulfate and concentrated to ca. 1 ml. FD-MASS analysis of the concentrate shows a peak at m / e β 286. This leads to the determination that the concentrate contains vitamin A (£).

The concentrate is dissolved in 2 ml of pyridine and cooled in an ice bath. 0.0137 g (0.05 mmol) of palmitoyl chloride is added to the solution and the mixture is stirred under cooling with an ice bath for 0.5 hour and then at room temperature for 5 hours. The reaction mixture is poured into a large amount of water and extracted with hexane. The hexane extract is washed with water and then dried over anhydrous magnesium sulfate. The magnesium sulfate is separated by filtration and the hexane is evaporated off

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DK 171415 B1 63 the filtrate at reduced pressure. As a result, 0.0282 g of a reddish yellow oil is obtained. The oil is determined to contain 0.0183 g of vitamin A palmitate from the results of liquid chromatography analysis (column: μ-porasil, 5 mobile phase: a 2: 98 mixture by volume of diisopropyl ether and hexane).

EXAMPLE 33 (A) ζΡζΡ 15 °

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o = s = o 20 OH 23 In a 200 ml flask flushed with argon gas, 8.70 g (31.2 mmol) of beta-cyclogeranyl phenylsulfone and 25 ml of tetrahydrofuran are charged and cooled to -78 ° C. Then, 20.8 ml (31.2 mmol) of a hexane solution of n - butyllithium (1.5 mol / liter) is added dropwise and the mixture is stirred at the above temperature for 3 hours. Then a solution of 6.59 g (31.3 mmol) of 8-acetoxy-2,6-30-dimethyl-2 (E), 6 (Z) -octadien-1-al in 15 ml of tetrahydrofuran is added dropwise at -78 And the mixture is stirred at this temperature for 2 hours. The mixture is further stirred at -50 ° C for 2 hours. The reaction mixture is cooled to -78 ° C and water is added. The temperature of the mixture is raised to room temperature. The resulting mixture is extracted with three 100 ml portions of benzene. The extracts are washed with water and dried

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DK 171415 B1 64 over anhydrous sodium sulfate. The benzene is evaporated from the extract and the residue is chromatographed on a silica gel column using an eluent composed of a mixture of hexane and ethyl acetate in a volume ratio of 5: 1 to give 13.87 g of a colorless transparent oil.

From the following analytical data, this product has been determined to be 1-acetoxy-8-hydroxy-3,7-dimethyl-9- (2,6,6-trimethyl-1-cyclohexen-1-yl) -9 -phenylsulfonyl-2 (Z), 6 (E) -nonadiene (23). Yield 91%.

CDCl 1, NMR (CH 3 T 3 SiOSi (CH 3) 3: 0.60-2.20 (m, 28H); 3.67 (br, 1H); 3.98 (d, 1H); 4.50 (d, 2H) 5.00 (d, 1H); 5.34 (m, 2H); 7.55-8.20 (m, 5H).

IR (film) (cm Χ): 3500 (OH), 1735 (C = O), 1140 (SO 2>).

FD MASS m / e: 488 (M +).

(B)

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20 · o = s = o rfj

Uk. j) B 23 p-TS0H

In a 100 ml flask, 4.88 g (10 mmol) of the compound (23), 0.02 g (0.1 mmol) of p-toluenesulfonic acid monohydrate and 30 ml of methylene chloride are charged. cool with a 35 ice-water bath. 2.6 ml (30 mmol) of 3,4-dihydro-2H-pyran are added dropwise. After the addition, the mixture is stirred at the above temperature for 2 hours.

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0.52 g of sodium bicarbonate is added to the reaction mixture. The mixture is stirred for 5 minutes and then 20 ml of a saturated aqueous solution of sodium bicarbonate is added. The resulting mixture is extracted with 5 100 ml of diethyl ether. The extract is washed with 20 ml of a saturated aqueous solution of sodium bicarbonate and dried over anhydrous magnesium sulfate. The solvent is evaporated by means of an evaporator and the residue chromatographed on a silica gel column using an eluent composed of a 1: 5 mixture of ethyl acetate and n-hexane to give 5.75 g of the compound (24) . Yield 100%. The analytical data of the product are as follows:

NMR

(CH 3 R 3 SiOSi (CH 3) 3: 0.60-2.02 (m, 34H); 3.17-5.40 (m, 9H); 7.38-8.11 (m, 5H).

IR (film) ν (cm -1): 1745 (C = O), 1150 (SO 2).

(C)

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o = s = o COME ^ 25 Ό - | ^ Α> Λ> ^ ν ^ νΝ> 0Η _ ^

Under an argon gas atmosphere, 0.5678 g (0.993 mmol) of the compound (24 ^), 15 ml of cyclohexane and 0.70 g (10 mmol) of potassium methoxide are charged to a 50 ml flask, and bianco 171715 B1 66

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the mixture is stirred for 1.5 hours at 40 ° C.

The reaction mixture is poured into a mixture of 50 ml of diisopropyl ether and 15 ml of a saturated aqueous solution of ammonium chloride and the organic layer is separated. The 5 organic layer is washed with 10 ml of a saturated aqueous solution of ammonium chloride and dried over anhydrous magnesium sulfate. The solvent is evaporated with an evaporator. The residue is dissolved in 4 ml of hexane and transferred to a 50 ml brown flask.

The flask is cooled in an ice-water bath and 1.1 ml of triethylamine and 0.68 ml of acetic anhydride are added. The mixture is stirred for one day at room temperature.

The reaction mixture is poured into a mixture of 50 ml of hexane and 10 ml of a saturated aqueous solution of sodium bicarbonate and the organic layer is separated. The organic layer is washed twice with 10 ml of a saturated aqueous solution of sodium bicarbonate and dried over anhydrous magnesium sulfate. The solvent is evaporated by means of an evaporator to give 0.3635 g of an orange oily product. For high performance liquid chromatography (column: μ-porasil, mobile phase: a 9: 1 mixture of hexane and diisopropyl ether), this oil type product is found to contain 0.248 g of vitamin A acetate (2) · Yield 76%. The yield of the 13-cis isomer 25 in the vitamin A acetate is 90%.

30 35

Claims (6)

A process for the preparation of vitamin A of the formula HC CH3 H3 ^ H3 5 3 *> <\ Jch «ch-c« = ch-ch = ch-c = ch-ch2oh 0 ^ C „3 characterized in that a compound of the general formula R1 0 = S = 0 pn ΛΜ HC CHJ, 3, 3 21 J> <JCH-CH-C = CH-CHoCH, -C = CH-CHoOR (IIa-2) 15 OC 0R3 ch3 R1 0sSs0 pu ru H, C CHj in H3, 3 21 20 J> <^ CH-CH = C-CH-CH., CH, -C = CH-CHoOR (Hb) OC in CH or J R1 25 H3C CH3 | °? H3? H3 22 -3> <^ C = CH-C = CH-CHOCH.-C = CH-CH.OR (Ile) <X, 1 2 3 4 5 6 where R1 represents a phenyl group optionally being substituents 2, R21 and R22 each represent a hydrogen atom or a 3 lower alkanoyl group, R3 represents a 4 acetal type protecting group for a hydroxyl group, and X represents a halogen 5 inch, treated with a base selected lower alkoxides of potassium 6 and potassium hydroxide in a solvent selected from aliphatic hydrocarbons and aromatic hydrocarbons and mixtures thereof. Process according to claim 1, characterized in that the base is potassium methoxide or potassium n-but oxide. Process according to claim 2, characterized in that the base is potassium methoxide. Process according to claim 1, characterized in that the treatment is carried out at a temperature of from 20 to 80 ° C. Process according to claim 1, characterized in that the treatment is carried out in an atmosphere of an inert gas. Process according to any one of claims 1-3, characterized in that the solvent 15 is selected from toluene, cyclohexane and mixtures thereof.